Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001754.5(RUNX1):c.895G>A (p.Ala299Thr)

CA320255506

1711954 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: db17c7aa-7246-4250-8106-fb02f9ba07ff
Approved on: 2024-07-25
Published on: 2024-07-25

HGVS expressions

NM_001754.5:c.895G>A
NM_001754.5(RUNX1):c.895G>A (p.Ala299Thr)
NC_000021.9:g.34799373C>T
CM000683.2:g.34799373C>T
NC_000021.8:g.36171670C>T
CM000683.1:g.36171670C>T
NC_000021.7:g.35093540C>T
NG_011402.2:g.1190339G>A
ENST00000675419.1:c.895G>A
ENST00000300305.7:c.895G>A
ENST00000344691.8:c.814G>A
ENST00000399240.5:c.622G>A
ENST00000437180.5:c.895G>A
ENST00000482318.5:c.*485G>A
NM_001001890.2:c.814G>A
NM_001754.4:c.895G>A
NM_001001890.3:c.814G>A
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Uncertain Significance

Met criteria codes 2
BP4 PM2_Supporting
Not Met criteria codes 15
BP7 BP1 BP2 PS4 PS2 PS1 PP3 PP2 PM1 PM5 PM3 PM6 PVS1 BA1 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.895G>A (p.Ala299Thr) is a missense variant which is absent from gnomAD v2 and v3 (PM2_supporting). This variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.112, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and BP4.
Met criteria codes
BP4
REVEL score = 0.112, which is less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PM2_Supporting
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
Not Met criteria codes
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No literature was found in LOVD, HGMD, ClinVar, COSMIC, and Mastermind.
PS2
No literature was found in LOVD, HGMD, ClinVar, COSMIC, and Mastermind.
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, and Mastermind.
PP3
REVEL score = 0.112, which is not higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM5
A299/A272 variants are reported in COSMIC and/or Mastermind, but not at a high enough frequency that they would be likely classified as LP/P.
PM3
Not applicable
PM6
No literature was found in LOVD, HGMD, ClinVar, COSMIC, and Mastermind.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
BS1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
Curation History
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